Reduccion de transmisión de VIH a la pareja serodiscordante heterosexual, cuando el caso indice toma TARGA

1. Enferm Infecc Microbiol Clin. 2015;33(10):666–672
www.elsevier.es/eimc
Brief report
Absence of transmission from HIV-infected individuals with HAART
to their heterosexual serodiscordant partners
Jorge Del Romeroa,∗
, Isabel Ríoc,d
, Jesús Castillab,c
, Bego˜na Bazaa
, Vanessa Paredesd
, Mar Veraa
,
Carmen Rodrígueza
a
Centro Sanitario Sandoval, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
b
Instituto de Salud Pública de Navarra, Pamplona, Spain
c
CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
d
Centro Nacional de Epidemiología, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
a r t i c l e i n f o
Article history:
Received 27 May 2014
Accepted 30 October 2014
Available online 30 December 2014
Keywords:
HIV
Sexual transmission
Antiretroviral therapy
HIV prevention
HIV serodiscordant couples
a b s t r a c t
Background: Further studies are needed to evaluate the level of effectiveness and durability of HAART to
reduce the risk of HIV sexual transmission in serodiscordant couples having unprotected sexual practices.
Methods: A cross-sectional study was conducted with prospective cohort of heterosexual HIV serodiscor-
dant couples where the only risk factor for HIV transmission to the uninfected partner (sexual partner)
was the sexual relationship with the infected partner (index case). HIV prevalence in sexual partners
at enrolment and seroconversions in follow-up were compared by antiretroviral treatment in the index
partner, HIV plasma viral load in index cases and sexual risk exposures in sexual partners. In each visit,
an evaluation of the risks for HIV transmission, preventive counselling and screening for genitourinary
infections in the sexual partner was performed, as well as the determination of the immunological and
virological situation and antiretroviral treatment in the index case.
Results: At enrolment no HIV infection was detected in 202 couples where the index case was taking
HAART. HIV prevalence in sexual partners was 9.6% in 491 couples where the index case was not tak-
ing antiretroviral treatment (p < 0.001). During follow-up there was no HIV seroconversion among 199
partners whose index case was taking HAART, accruing 7600 risky sexual exposures and 85 natural preg-
nancies. Among 359 couples whose index case was not under antiretroviral treatment, over 13,000 risky
sexual exposures and 5 HIV seroconversions of sexual partners were recorded. The percentage of sero-
conversion among couples having risky sexual intercourse was 2.5 (95% confidence interval [CI]: 1.1–5.6)
when the index case did not undergo antiretroviral treatment and zero (95% CI: 0–3.2) when the index
case received HAART.
Conclusions: The risk of sexual transmission of HIV from individuals with HAART to their heterosexual
partners can become extremely low.
© 2014 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Enfermedades
Infecciosas y Microbiología Clínica.
Ausencia de transmisión del VIH desde individuos infectados y bajo TARGA
a sus parejas heterosexuales serodiscordantes
Palabras clave:
VIH
Transmisión sexual
Terapia antirretroviral
Prevención del VIH
Parejas heterosexuales serodiscordantes
al VIH
r e s u m e n
Introducción: Son necesarios más estudios que evalúen el nivel de efectividad del TARGA y su duración
para prevenir la transmisión sexual del VIH en parejas serodiscordantes que tienen prácticas sexuales sin
protección.
Métodos: Estudio transversal y cohorte prospectiva de parejas heterosexuales serodiscordantes al VIH
en las cuales el único factor de riesgo para la transmisión del VIH al sujeto no infectado (contacto) fue la
relación sexual con el sujeto infectado (caso índice). Se estudió la prevalencia del VIH al inicio y las sero-
conversiones durante el seguimiento comparándolas en función de si el caso índice recibía tratamiento
∗ Corresponding author.
E-mail address: jromero@salud.madrid.org (J. Del Romero).
http://dx.doi.org/10.1016/j.eimc.2014.10.020
0213-005X/© 2014 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica.
Document downloaded from http://www.elsevier.es, day 18/12/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

2. J. Del Romero et al. / Enferm Infecc Microbiol Clin. 2015;33(10):666–672 667
antirretroviral, la carga viral plasmática del VIH del caso índice y las exposiciones sexuales de riesgo del
contacto. En cada visita se realizó una evaluación de riesgos para el VIH, consejo preventivo y despistaje
de infecciones genitourinarias en el contacto, y se determinó la situación inmunológica, virológica y el
tratamiento antirretroviral del caso índice.
Resultados: Al reclutamiento no se detectó ninguna infección en las 202 parejas cuyo caso índice recibía
TARGA, mientras que entre las 491 con caso índice sin tratamiento, la prevalencia fue del 9,6% (p < 0,001).
Durante el seguimiento no hubo seroconversiones en 199 parejas con caso índice bajo TARGA, aunque
tuvieron 7.600 exposiciones sexuales no protegidas y 85 gestaciones naturales. Entre las 359 parejas con
caso índice sin tratamiento se registraron más de 13.000 exposiciones sexuales de riesgo y 5 serocon-
versiones. Cuando el caso índice no recibía tratamiento, el porcentaje de seroconversión en parejas con
prácticas sexuales de riesgo fue 2,5% (IC 95%: 1,1–5,6) y cero cuando recibía TARGA (IC 95%: 0–3,2)
Conclusiones: El riesgo de transmisión sexual del VIH de personas tratadas con TARGA a sus parejas
heterosexuales puede llegar a ser extremadamente bajo.
© 2014 Publicado por Elsevier España, S.L.U. en nombre de Sociedad Española de Enfermedades
Infecciosas y Microbiología Clínica.
Introduction
HIV plasma viral load is the major risk factor for heterosex-
ual transmission of HIV.1–3 Highly active antiretroviral therapy
(HAART) can reduce HIV/RNA to undetectable levels in plasma4 and
genital fluids.5 Data suggest that HIV-infected people with persis-
tent undetectable viral load are much less infectious, and may be
less likely to transmit HIV to their sexual partners.6,7 Results of
recent studies indicate that HAART can have an important role in
the prevention of heterosexual transmission of HIV.8,9 There are
few prospective studies in HIV serodiscordant couples in developed
countries.10
A cohort of heterosexual serodiscordant couples was launched
in 1989 in Madrid and about one thousand couples had been
enrolled up to 2010. In preliminary results published in 2005, 2009
and 2010,6,11,12 we described a very important reduction in the
probability of sexual HIV transmission when the infected (index)
partner was receiving HAART. These preliminary results were con-
sistent with other relevant observational studies.7,13 Subsequently,
a large randomized multicentre clinical trial indicated that early
initiation of HAART drastically reduces the rates of heterosexual
HIV transmission.14 These results seem to confirm the individual
and public health preventive benefits of effective HAART. However,
researchers agree that further research is needed to determine if the
level and durability of protection conferred by HAART differs in the
presence of other factors affecting sexual HIV transmission such as
unprotected sexual practices and genitourinary infections.10,15
The aim of this study was to help elucidate some of these issues
in light of the most recent data from the Madrid cohort of het-
erosexual HIV serodiscordant couples. Therefore, we analyzed the
baseline prevalence of HIV infection in the sexual partners, HIV
incidence throughout follow-up, and the probability of transmis-
sion according to whether the index case received antiretroviral
treatment or not, HIV viral load in the index case and sexual risk
exposures in the sexual partner.
Methods
Setting and study population
Couples participating in this study were included in a specific
programme for heterosexual HIV serodiscordant couples launched
in 1989 in a clinic for sexually transmitted infections (STIs) in
Madrid, Spain. Each new patient diagnosed with HIV infection was
advised that his or her sexual partner should visit the clinic. The pro-
gramme includes scheduled six-monthly check-ups. At each visit,
the index case undergoes clinical follow-up, and is provided access
to free antiretroviral treatment meeting current international and
local guidelines in use during each period. The sexual partner is
recommended to undergo an HIV test and screening for genitouri-
nary infections. Couples are systematically advised against having
unprotected sex, and they receive free condoms.
The protocol of this study was approved by the Clinical Research
Ethics Committee of the Hospital Clínico San Carlos in Madrid,
Spain. The patients were informed about the aim of the study and
they agreed to participate by signing an informed consent.
A cross-sectional analysis of HIV prevalence in sexual partners
was carried out at recruitment, including all heterosexual couples
between 1989 and 2010 who met the following criteria: on-going
sexual relationship during at least the past six months, well known
clinical and therapeutic status of the index case, and no known risk
exposure other than the heterosexual relationship with the index
case. After informed consent of both partners, stable heterosex-
ual couples who were serodiscordant for HIV in the first visit and
who returned for at least one follow-up visit were included in an
observational prospective cohort analysis to quantify the risk of
heterosexual HIV transmission according to sexual risk exposures
in the sexual partner and antiretroviral therapy in the index case.
Follow-up began on the date of the first negative HIV test result for
the sexual partner, and the end point was a positive HIV test result.
Data were censored at the last follow-up visit for participants who
failed to return for check-ups for more than 24 months, whose rela-
tionship ended, or whose sexual partner reported any risk exposure
outside the relationship. For the remaining couples, follow-up was
censored at the last check-up before 31 December 2010.
Trained physicians used specific forms in each visit to col-
lect information on epidemiological, clinical and sexual behaviour.
They asked sexual partners the total number of sexual intercourses
(vaginal and anal intercourses) during the previous six months (at
recruitment) or since the previous visit (at follow-up). Respon-
dents reported the number of unprotected sexual contacts (without
condom) using a semi-quantitative scale (never, less than half of
the times, more than half of the times or always); coefficients
0, 0.33, 0.67 and 1 were assigned, respectively, to this scale in
order to estimate the frequency of “risky sexual practices”. Overall,
unprotected sexual risk practices and condom breakage or slip-
page during intercourse were considered “risky sexual exposures”.
Couples were categorized in each visit according to antiretrovi-
ral treatment received by the index case: not taking antiretroviral
treatment, taking mono/dual therapy, and taking HAART.
Laboratory tests
At baseline and every visit thereafter serum antibodies to
HIV-1/2 were determined in the sexual partners, and reactive
samples were confirmed by western blotting. CD4 count in the
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3. 668 J. Del Romero et al. / Enferm Infecc Microbiol Clin. 2015;33(10):666–672
Table 1
Characteristics of couples enrolled during 1989–2010 according to treatment of index case.
Antiretroviral treatmenta
Total No treatment Combined treatment p valueb
All 716 (100) 491 (100) 202 (100)
Male index case 585 (82) 394 (80) 171 (85) 0.2
History of injecting drug use in index case 516 (72) 372 (76) 126 (62) <0.001
Median (IQR) age (years) index cases (Women) 32 (27–36) 29 (25–33) 36 (33–41) <0.001
Median (IQR) age (years) index cases (Men) 32 (28–38) 30 (27–34) 38 (34–42) <0.001
Median (IQR) age (years) non-index cases (Women) 29 (25–35) 27 (23–32) 30 (27–35) <0.001
Median (IQR) age (years) non-index cases (Men) 33 (29–38) 31 (27–36) 32 (28–38) <0.001
Median (IQR) length of the relationship (years) 3.3 (0.9–7.9) 2.7 (0.8–7.4) 4.6 (1.9–10.1) <0.001
Median (IQR) known duration of HIV infection (months) 31 (3–105) 11 (1–43) 130 (60–190) <0.001
Detectable plasma HIV RNA in index casec
156 (52) 122 (93) 32 (21) 0.01
Median (IQR) plasma HIV RNA copies per ml in index casec
125 (ND–3376) 7303 (1392–28,916) ND <0.001
Median (IQR) CD4 cell count ×106
/L in index cased
505 (300–696) 542 (341–746) 500 (296–647) 0.4
Unprotected coital acts in past 6 months 383 (53) 280 (57) 93 (46) 0.01
Number of HCV+ index casese
334 (46.6) 188 (38.3) 125 (61.9) 0.01
Current sexually transmitted infection in either partner 57 (8) 35 (7) 21 (10) 0.2
Current bacterial vaginosis or candida vaginitis in the woman 100 (14) 72 (15) 16 (8) 0.02
HIV infection in sexual partner 49 (6.8) 47 (9.6) 0 <0.001
Figures are numbers (percentages) of participants unless stated otherwise.
IQR = interquartile range; ND = non-detectable plasma HIV RNA.
a
Couples with index case taking monotherapy or dual therapy are not shown (n = 23).
b
p values were obtained from Fisher’s exact test or Wilcoxon’s test.
c
Available for 302 patients.
d
Available for 640 patients.
e
21 HCV+ index cases were under monotherapy or dual therapy.
index case was determined by flow cytometry and plasma HIV
RNA by a branched DNA assay. The lower limit of detection was
500 copies/mL until 1999, and 50 copies/mL thereafter. Syphilis was
routinely evaluated by reaginic (RPR) and treponemic (ELISA and
TPPA or FTA-abs) tests. Others STIs were evaluated in men having
signs/symptoms or whose partners had been diagnosed with an STI.
Gynaecological examinations included STI screening in cervical and
vaginal exudates.
Statistical analysis
HIV prevalence at enrolment in sexual partners was observed
and a stratified analysis by selected characteristics of the couples
was performed to rule out the main potential confounding fac-
tors in the association between HIV prevalence in sexual partners
and treatment in index cases. In the follow-up analysis, we quan-
tified some characteristics of the couples, events occurring during
follow-up and the number of new HIV seroconversions. Moreover,
we estimated the incidence rate of seroconversion by couple-years
of follow-up and the probability of transmission per sexual risk
exposure between two successive visits among those receiving
HAART, mono/dual therapy with nucleoside analogue reverse-
transcriptase inhibitors (NRTIs) or without treatment. Index cases
who started or changed antiretroviral treatment between two
successive visits were classified in the less effective treatment cate-
gory. Genitourinary infections and other circumstances detected at
a visit were considered as covariates present during the whole time
period since the previous visit. Continuous variables were com-
pared with the Wilcoxon test, proportions with the Fisher’s exact
test and rates with exact methods. Interquartile ranges (IQR) for
medians, 95% confidence intervals (CIs) for rates (assuming a Pois-
son distribution) and risks (assuming a binomial distribution) were
calculated.
Results
HIV prevalence at enrolment
Between 1989 and 2010, 716 heterosexual couples, in which
only one partner had previously received a diagnosis of HIV
infection, were recruited for this study. Characteristics of these
couples according to treatment of the index case (no treatment
or HAART) are showed in Table 1. In 585 (82%) couples the index
case was a man and in 516 (72%) the index case had a history
of injecting drug use (IDU). The median length of the relation-
ship was 3.3 years. In 491 (69%) couples the index case was not
taking any antiretroviral treatment: in 333 because antiretrovi-
ral drugs were not yet available, in 135 who did not meet the
criteria for treatment and in 23 who declined treatment. Among
the index cases receiving antiretroviral therapy, 23 were under
mono/dual therapy receiving only NRTIs and 202 were receiving
HAART. HIV viral load was detectable in 93% (122/131 with viral
load data) of the index cases who were not taking antiretrovi-
ral treatment compared to 21% (32/152 with viral load data) of
those undergoing HAART (p = 0.01). The median of VL in these last
couples was 1238 (IQR = 687–21,599). The proportion of couples
having unprotected sexual intercourses was lower among those
whose index case was taking HAART (93/202 (46%) vs 280/491
(57%), p = 0.01). Among the 32 couples with index cases under
HAART and detectable VL, only six reported unprotected sexual
practices. Index cases of these couples were less than one year
under HAART. Overall, 334 (46.6%) index cases were HCV+, most
of them (90.7%) ex-IDU. They represented 38.3% of the untreated
index cases and 61.9% of those under HAART (p < 0.001). Although
there was no significant difference in the proportion of current
STIs in either partners according to antiretroviral treatment of the
index case, the prevalence of bacterial vaginosis/candida vaginitis
was significantly higher among women in couples in which the
index case was not being treated (72/491 (15%) vs 16/202 (8%),
p = 0.02).
HIV prevalence in sexual partners was 6.8% (49/716) overall: 11%
(38/352) among those diagnosed in 1989–1996 and 3% (11/364)
in persons diagnosed in 1997–2010, when HAART was available
(p < 0.001). The prevalence of HIV infection was 9.6% (47/491)
in couples where the index cases were not taking antiretroviral
treatment and 8.7% (2/23) among partners of index cases taking
mono/dual therapy, but no HIV infection was detected in partners
of index cases taking HAART (0/202; p < 0.001) (Fig. 1). The strat-
ified analyses by selected characteristics of the couples shown in
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4. J. Del Romero et al. / Enferm Infecc Microbiol Clin. 2015;33(10):666–672 669
12
10
8
6
4
2
9.6
8.7
Follow-up n=469First visit n=716
0
Not ART
47/491
HAART
0/202
Mono/dual ART
2/23
0
%HIV+(non-indexpartners)
12
10
8
6
4
2 1.4
0 0
Not ART
5/359
886 couple-years.
13 000 unprotected coitus
57 natural pregnancies
75 couple-years.
1600 unprotected coitus
8 natural pregnancies
514 couple-years.
7600 unprotected coitus
85 natural pregnancies
HAART
0/199
Mono/dual
0/47
0
%HIV+(non-indexpartners)
Fig. 1. Study scheme of couples included in each analysis.
Table 2 excluded the main potential confounding factors for this
last association.
HIV seroconversions during follow-up
HIV transmission was evaluated in 469 couples who were
serodiscordant at recruitment and who had at least one follow-
up visit. About 20% of couples met criteria for censored follow-up:
five HIV seroconversions, 23 deaths of a partner, 46 ended rela-
tionships and 18 sexual partners who had sexual contacts with
another person. About 57% of the couples in follow-up did not
return for a check-up in 24 months, whereas 24% were still in
follow-up in December 2010. Characteristics of couples and events
occurring during follow-up according to antiretroviral treatment
are shown in Table 3. Median follow-up time was 2.2 years (IQR:
0.8–4.3), and 42% of couples were followed between two and
21 years. Median follow-up for couples with the index case under
HAART was also 2.2 years (IQR: 0.6–4.0). A total of 1475 couple-
years of follow-up were accrued. About 110,000 coital acts were
estimated (6.2 per month), of which 22,200 were risky sexual
Table 2
Prevalence of HIV infection at first visit among sexual partners, according to selected characteristics of the couples.
Population analyzed No antiretroviral treatment Combined antiretroviral treatment p value*
Variables Category Infected/analyzed HIV prevalence (%) Infected/analyzed HIV prevalence (%)
All index cases 47/491 10 0/202 0 <0.001
Index case male 40/394 10 0/171 0 <0.001
Index case female 7/97 7 0/31 0 0.2
Beginning of relationship
After HIV diagnosis in index
case
12/168 7 0/137 0 <0.001
Before HIV diagnosis in index
case
35/323 11 0/65 0 0.002
Time since beginning of
relationship (years)
<5 30/314 10 0/108 0 <0.001
≥5 17/177 10 0/94 0 0.003
Plasma HIV RNA in index case
Not detectable 0/9 0 0/164 0 1
Detectable 8/119 7 0/32 0 <0.001
Not available 39/360 11 0/7 0 1
CD4 cell count per 106
/L in
index case
≥200 21/365 6 0/182 0 <0.001
<200 11/60 18 0/15 0 <0.001
Not available 15/66 23 0/5 0 0.6
AIDS defining conditions in
index case
No 34/439 8 0/93 0 0.002
Yes 13/52 25 0/109 0 <0.001
Genitourinary infection in
either partner
No 36/389 9 0/167 0 <0.001
Yes 11/102 11 0/35 0 0.1
Period
1989–96 36/334 11 0/0 NA NA
1997–2010 (combined
treatment available)
11/157 7 0/202 0 <0.001
Figures are numbers and percentages.
NA = not available.
*
p values obtained from two-sided Fisher’s exact test comparing index cases who were not taking antiretroviral treatment and those undergoing HAART.
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5. 670 J. Del Romero et al. / Enferm Infecc Microbiol Clin. 2015;33(10):666–672
Table 3
Characteristics of the couples and events occurring during follow-up according to antiretroviral treatment of index case.
Antiretroviral treatment of index casea
All couples Without treatment Mono/dual therapy Combined treatment
All 469 359 47 199
Male index case (%) 385 (82) 298 (83) 33 (70) 160 (80)
Median (IQR) follow-up (years) 2.2 (0.8–4.3) 2.1 (0.8–4.3) 2.8 (1.1–4.8) 2.2 (0.6–4.0)
Couple-years 1475 886 75 514
Estimated number of coital acts 110,000 67,000 7000 36,000
Estimated number of risky sexual exposuresb
22,200 13,000 1600 7600
Couples with unprotected coital acts (%) 328 (70) 204 (57) 33 (70) 115 (58)
Couple-years with unprotected coital acts 858 464 32 362
Number of condom failures during intercourse 210 166 14 30
Plasma HIV RNA (undetectable/tested) (%) 177/247 (72) 52/201 (26) 6/17 (35) 119/128 (93)
Median (IQR) plasma HIV RNA copies per ml ND (ND–6900) 4069 (500–15,344) 5367 (ND–16,770) ND
Sexually transmitted infection in either partner 9 8 1 2
Women with bacterial vaginosis or candida
vaginitis
61 53 9 6
Number of seroconversions 5 5 0 0
Percentage of couples with seroconversion (95% CI) 1.1 (0.4–2.5) 1.4 (0.6–3.2) 0 (0–7.6) 0 (0–1.9)
Rate of seroconversion per 100 couple-years
(95% CI)
0.3 (0.1–0.8) 0.6 (0.2–1.3) 0 (0–4.9) 0 (0–0.7)
Percentage of seroconversion in couples with risky
sexual exposures (95% CI)
1.5 (0.7–3.5) 2.5 (1.1–5.6) 0 (0–10.4) 0 (0–3.2)
Transmission per 1000 risk exposures (95% CI) 0.2 (0.1–0.5) 0.4 (0.2–0.9) 0 (0–2.4) 0 (0–0.5)
Number of natural pregnancies 150 57 8 85
IQR = interquartile range; ND = not detectable; CI = confidence interval.
a
Each couple could have different therapeutic options during follow-up.
b
Includes coital acts without condom and condoms breaking or slipping during intercourse.
exposures (1.3 per month). During one or more follow-up periods,
70% of couples reported unprotected sexual contacts, and 210
condom failures were reported among couples who always used
condoms. There were about 13,000 sexual risk exposures (166
condom failures) in 886 couple-years when the index case was
not taking antiretroviral treatment, and the median HIV plasma
viral load was 4069 copies/mL (IQR: 500–15,344). Bacterial vagi-
nosis/candida vaginitis was detected in 15% of women in these
couples.
The index case was taking HAART in 199 couples during 514
couple-years, accruing over 7600 sexual risk exposures (30 condom
failures), and 93% (119/128) of index cases had undetectable plasma
HIV RNA. Bacterial vaginosis/candida vaginitis was diagnosed in 3%
of women in these couples. There were five HIV seroconversions of
sexual partners among 359 couples whose index case was not tak-
ing HAART, and no seroconversion among those whose index case
was taking it. The ratio of HIV transmission per 1000 risk exposures
was 0.4 for the couples with index cases without antiretroviral
treatment and zero for those receiving HAART. The percentage of
seroconversion among couples having risky sexual exposures was
2.5 (95% CI: 1.1–5.6) when the index case was not under antiretro-
viral treatment and zero (95% CI: 0–3.2) when he or she received
HAART (Table 3). There was, however, no significant difference
between the probability of transmission of index partner with and
without HAART (p = 0.17).
Characteristics of couples in which HIV transmission occurred
Overall, HIV transmission was detected in 54 couples; 49 of
these transmissions were identified at enrolment and five during
follow-up (Table 4). Two of the 54 index cases were being treated
with one antiretroviral drug, but none was receiving HAART. Three
couples (two at enrolment and one at follow-up) had not reported
any unprotected intercourse, and transmission was associated
with condom failure. None of them received antiretroviral post-
exposure prophylaxis. In 12 couples (22%) one or both partners
had genitourinary infections: in index cases the most frequent
were urethritis, syphilis, genital warts, vaginitis and genital her-
pes; in sexual partners cervicitis, it was genital warts and genital
herpes. Plasma HIV RNA was measured in nine transmitter part-
ners and all of them had a detectable concentration, ranging from
362 to 257,325 copies/mL. Three of the five transmissions dur-
ing follow-up occurred before the availability of VL. In the other
Table 4
Characteristics of 54 couples with diagnosis of HIV infection in the sexual partner.
N (%)
Median (IQR) age (years) for women 26 (21–31)
Median (IQR) age (years) for men 29 (24–33)
Median (IQR) time of relationship
(years)
4.8 (1.3–7.4)
Began relationship after HIV diagnosis
in index case
16 (30)
Median (IQR) time since HIV diagnosis
(months) in the index case
8 (1–51)
Index case male 46 (85)
Index case Injecting drug user 41 (76)
Median (IQR) last CD4 cell count
×106
/L (n = 36) in the index-partner
273 (133–464)
Median (IQR) last plasma HIV RNA
copies per ml (n = 9) in the
index-partner
30,210 (11,076–73,122)
Index case receiving monotherapy 2 (4)
Index case not receiving treatment 52 (96)
Coital acts without condom 51 (94)
Failure of condom during intercourse
as sole risk exposure
3 (5)
Genitourinary infection in either
partner
12 (22)
Pregnancy 5 (9)
Transmission detected during
combined antiretroviral treatment
period
13 (24)
Figures are numbers (percentages) of participants or median (interquartile range).
IQR = interquartile range.
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6. J. Del Romero et al. / Enferm Infecc Microbiol Clin. 2015;33(10):666–672 671
two transmissions the index cases had a viral load of 35,410 and
73,122 copies/mL, respectively.
Discussion
Our study revealed that no index case receiving HAART trans-
mitted the HIV infection to his or her heterosexual partner. No cases
of transmission were found either among the 202 couples ana-
lyzed at the first visit in which the index case was taking HAART, or
among the 199 that were followed during 514 couple-years. This
allows us to establish, with less than 5% error, that the probability of
HIV transmission among couples where the index case was under
HAART is lower than 1 in 2000 risk exposures, and the rate of sero-
conversion is less than 1 in 100 couple-years. Conversely, among
couples whose index case was not taking HAART, we detected
49 HIV infections at the first visit and five during follow-up. This
represents 2.5 HIV transmissions per 100 couples having risky sex-
ual exposures whose index case was not receiving treatment. The
Madrid cohort of heterosexual HIV serodiscordant couples is one of
the most representative cohorts of this type in developed countries.
Our previous study12 is the only one to report sexual HIV-1 trans-
mission stratified by antiretroviral treatment use in a high income
country.10 A prominent feature of the present study is the consid-
erably long follow-up, a median of 2.2 years (IQR: 0.8–4.3), higher
than that reported in other relevant studies.13,14 About 42% of our
couples were followed up between two and 21 years, and around
25% of those where the index case was under HAART were followed
for four or more years.
In our study, sexual behaviour data are collected in a detailed
and exhaustive way. This allowed us to estimate a very large num-
ber of risky sexual exposures (22,200) occurring in 70% of couples
during one or more follow-up. This high proportion of couples
having unprotected sex differs from the results reported in other
studies.13–15 Recently, preliminary results of the Partner Study pre-
sented in the CROI 2014 conference showed similar results to ours,
with an estimated total number of condomless vaginal sex acts
of 28,000 in 485 heterosexual couples with VL <200 copies/mL.16
A partial explanation for this difference could be that participants
in cohort studies probably exhibit greater behavioural similarities
to serodiscordant couples in the general population than to those
enrolled in clinical trials. Moreover, longer follow-up periods could
result in increased instances of unsafe sex. In addition, in 2002 a
counselling programme for HIV serodiscordant couples with repro-
ductive desire by natural means was launched in our clinic, and
in our study 18% of couples carried out at least one reproductive
attempt during the follow-up period, resulting in 150 pregnan-
cies, 85 of them in couples whose index case was under HAART.
Studies in heterosexual HIV serodiscordant couples with viral sup-
pression have reported, in all, a follow-up of 330 couple-years when
condoms were not being used.15 Our results, reporting 362 couple-
years not using condoms, attempt to help meet the need for studies
with longer follow-up.
One hundred and forty-one couples reported systematic use of
condoms and one accident (breakage or slippage) as the only risk
exposure. In three of these couples, two at recruitment and one at
follow-up, the index cases were not receiving antiretroviral treat-
ment and condom failure resulted in the transmission of HIV to
their sexual partners. In contrast, zero transmissions were found
in couples having risky sexual exposures when the index case was
taking HAART. Several meta-analyses of observational and cohort
studies have found that 100% condom use reduces HIV transmission
in heterosexual couples by about 80%.17 The HPTN 052 study has
reported a 96% reduction when the HIV-positive partner was taking
HAART.14 The studies conducted to date on heterosexual serodis-
cordant couples indicate that the small number of documented
HIV transmissions occurred from individuals who had recently
started therapy and in whom it is unlikely that undetectable viral
load was achieved.13,14,18 Our previous study,12 together with two
others,8,19 have been identified20 as the only ones in which full viral
suppression was confirmed in the index cases under HAART. Pooled
transmission rate for these studies was zero per 100 person-years
(95% CI: 0–0.05).
Couples in our study maintained a closed and stable relation-
ship for a median of 3.3 years, which justifies the relatively low
proportion of STIs at recruitment (8%). While no changes were
reported in other studies,14 STI incidence decreased considerably
during follow-up (2%), probably as a result of our testing and coun-
selling programme.11 STIs and other genitourinary infections can
increase the probability of HIV transmission.1,21–25 Indeed, among
couples in which STIs or genitourinary infections were diagnosed
in one or both members, 12 HIV transmissions occurred when the
index case was not treated. However, there was no HIV transmis-
sion when the index case was taking HAART. A high prevalence of
HCV+ was identified at enrolment in the index cases, something
related to the presence in our cohort of people with a history of
IDU.
Our study has several limitations. HIV plasma viral load was
only quantified in 9 of 54 couples in which a new HIV infection
was detected, because most of them were diagnosed before 1996
when viral load testing was not yet available. Data were insuffi-
cient to respond clearly to the question about the actual risk of HIV
transmission in the presence of STIs when HIV viral load is fully
suppressed by HAART. In HIV seroconcordant couples, we could
not assess whether viruses in both partners were genetically linked
because in most of the cases phylogenetic analysis was not avail-
able. The index cases without HAART, in general, had no indication
for treatment and had a relatively low VL; therefore, they are not
representative of all HIV infected population without HAART.
In conclusion, our results suggest that HAART is highly effective
to prevent the sexual HIV transmission in heterosexual serodiscor-
dant couples where the infected partners have sustained plasma
viral load suppression even when they practise unprotected sex.
Thus, although consistent condom use has a considerable pro-
tective effect in the population, the preventive impact of HAART
may be higher. In agreement with the latest WHO recommenda-
tions for treatment and prevention in serodiscordant couples,26
among other aspects such as the personalized preventive coun-
selling, antiretroviral therapy should be offered to the HIV positive
partner, regardless of his or her immune status, to reduce the like-
lihood of sexual HIV transmission.
Conflict of interest
The authors declare no conflict of interests.
Funding
This work was funded by the I Fellowship Programme, Gilead
Spain and the Ministry of Economy and Competitiveness (grant
CSO2011-26245).
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